Module 2
Asthma Assignment
a. Epidemiology
An estimated 26.5 million persons in the United States have asthma (about 8.4%
of the population).4 Asthma is the most common chronic disease among children in the
United States affecting overall health, with approximately 6 million children affected.5,6
In the United States, as in other industrialized countries, the prevalence of asthma has
increased from 7.3% in 2001. Asthma prevalence is higher in persons with incomes
below 100% of poverty level at 11.8% and in blacks 11.6% and Puerto Ricans 14.3%.
Adults are five times more likely to die from asthma than children, with the highest death
rates in females and non-Hispanic blacks (who have two to three times the death rate of
whites or Hispanics).5 Nearly 14 million school days are missed per year due to asthma,
and asthma accounts for nearly half of school absences in children with little variation by
sex, age (young vs adolescent), race and ethnicity, or poverty level.
Influenza infection can result in serious complications in people with asthma,
even those with mild disease and those who are well-controlled on medication. An annual
influenza vaccination is an essential preventative measure in people with asthma.
However, in 2015, only 47% of adults and 64% of children with asthma received the
influenza vaccination, with the highest rate in children under 5 years at 80%, which is
likely due to regular visits to the pediatrician.5 Approximately 60% of adults and children
describe themselves as having persistent (vs intermittent) asthma yet only 40% of adults
and children report using long-term control medications that are fundamental for the
prevention and control of symptoms. Nearly 20% of children and 24% of adults report
using a quick-relief medication (such as a short-acting inhaled β2 -agonist [SABA]) more
than twice weekly, which is a marker for poorly controlled asthma.
Influenza infection can result in serious complications in people with asthma,
even those with mild disease and those who are well-controlled on medication. An annual
influenza vaccination is an essential preventative measure in people with asthma.
However, in 2015, only 47% of adults and 64% of children with asthma received the
influenza vaccination, with the highest rate in children under 5 years at 80%, which is
likely due to regular visits to the pediatrician.5 Approximately 60% of adults and children
describe themselves as having persistent (vs intermittent) asthma yet only 40% of adults
and children report using long-term control medications that are fundamental for the
prevention and control of symptoms. Nearly 20% of children and 24% of adults report
using a quick-relief medication (such as a short-acting inhaled β2 -agonist [SABA]) more
than twice weekly, which is a marker for poorly controlled asthma.
The natural history of asthma is still not well defined. Although asthma can occur
at any time, it is principally a pediatric disease, with most patients being diagnosed by 5
years of age and up to 50% of children having symptoms by 2 years of age.3 Asthma is
more common in boys but between 30% and 70% of children with asthma will improve
markedly or become symptom-free by early adulthood; chronic disease persists in about
30% to 40% of patients, but becomes more common in adult women than men; generally
20% or less develop severe chronic disease.3,9 Predictors of persistent adult asthma
include atopy, onset during school age, and presence of bronchial hyper-responsiveness
(BHR).3 Diminished lung growth may occur in some children (approximately 10%) with
asthma.
In adults, most longitudinal studies have suggested a more rapid rate of decline in
lung function in asthmatics than in nonasthmatic people, primarily reflected in forced
expiratory volume in 1 second (FEV1 ).3 However, the annual decline in FEV1 is less
than that in smokers or in patients with a diagnosis of emphysema. In general, individuals
with less frequent asthma attacks and normal lung function on initial assessment have
higher remission rates, whereas smokers have the lowest remission and highest relapse
rates.3 The level of BHR tends to predict the rate of decline in FEV1 , with a greater
decline found with high levels of BHR.
Airway obstruction in asthma is a significant concern that can have profound
implications for patients. This obstruction may become irreversible over time, a process
often linked to airway remodeling. Airway remodeling refers to the structural changes
that occur in the bronchial walls of patients with chronic asthma. These changes include
thickening of the airway walls, increased mucus production, and fibrosis, which
collectively contribute to the narrowing of the airways and the persistence of symptoms.
Airway remodeling can be triggered by ongoing inflammation and repeated
asthma attacks, which induce a cycle of damage and repair in the airways. Inflammatory
cells, such as eosinophils and mast cells, release cytokines and growth factors that
stimulate the proliferation of smooth muscle cells and the deposition of extracellular
matrix proteins. This results in the thickening of the airway walls and increased rigidity,
making the airways less responsive to bronchodilators and other treatments.
The progression of airway remodeling is variable among asthma patients. Some
individuals may experience significant remodeling early in the course of their disease,
while others may have minimal changes even after many years of living with asthma.
Factors that influence the extent of airway remodeling include genetic predisposition,
environmental exposures, and the severity and frequency of asthma exacerbations.
Despite these potential changes in the airway structure, it is important to note that
most patients with asthma do not experience a decrease in life expectancy due to the
long-term progression of their disease. Advances in asthma management, including the
use of inhaled corticosteroids, long-acting bronchodilators, and biologic therapies, have
significantly improved the control of asthma symptoms and reduced the frequency of
severe exacerbations. Regular monitoring and personalized treatment plans are essential
in preventing and minimizing airway remodeling.
Moreover, asthma education and self-management strategies empower patients to
recognize early signs of worsening asthma and to take appropriate action to prevent
severe attacks. This proactive approach contributes to better overall outcomes and quality
of life for asthma patients.
In conclusion, while airway obstruction in asthma can potentially become
irreversible and worsen over time due to airway remodeling, the majority of patients can
manage their condition effectively with appropriate treatment. This management ensures
that their life span is generally comparable to that of the general population. Continuous
advancements in asthma research and treatment hold promise for even better control of
the disease in the future, further reducing the impact of airway remodeling and improving
patient outcomes.
As with prevalence and morbidity, mortality from acute exacerbations of asthma
worldwide has been relatively stable over the past 10 years, with a death rate of 0.19 per
1,000 persons with asthma reported in 2012.10 However, those in the lowest
sociodemographic groups bear the greatest risk of death from asthma which may be more
than fivefold greater than those in the highest sociodemographic group.9 Despite the
relatively low number of asthma deaths, 80% to 90% are preventable.3 Most deaths from
asthma occur outside the hospital, and death is rare after hospitalization. The most
common cause of death from asthma is inadequate assessment of the severity of airway
obstruction by the patient or healthcare professional and inadequate therapy.
The most common cause of death in hospitalized patients with asthma is often
attributed to inadequate or inappropriate therapy. This highlights a critical aspect of
asthma management and underscores the importance of proper and timely medical
intervention. Inappropriate therapy can include a range of issues such as incorrect
medication usage, insufficient dosing, failure to adhere to prescribed treatments, or delays
in receiving appropriate medical care. These lapses can lead to severe asthma
exacerbations, which may progress to life-threatening respiratory failure if not managed
promptly and effectively.
The key to preventing deaths from asthma lies in rigorous adherence to treatment
guidelines and proactive management strategies. Both the United States National Asthma
Education and Prevention Program (NAEPP) and the Global Initiative for Asthma
(GINA) advocate for comprehensive asthma management plans that emphasize early
intervention, patient education, and regular monitoring. These guidelines stress the
importance of personalized treatment plans that are tailored to the individual needs of
each patient, taking into account factors such as the severity of asthma, comorbid
conditions, and response to treatment.
Education plays a pivotal role in asthma management. Patients and their families
must be well-informed about the nature of asthma, the importance of adherence to
medication regimens, and how to recognize early signs of worsening asthma. This
includes understanding how to use inhalers correctly, the role of maintenance versus
rescue medications, and the importance of avoiding known triggers. Educating patients
about the use of peak flow meters to monitor their lung function at home can also provide
early warning signs of an impending asthma attack, allowing for timely intervention.
Regular follow-up with healthcare providers is essential to ensure that asthma
control is maintained and that treatment plans are adjusted as needed. This includes
periodic reassessment of asthma control, lung function tests, and reviews of medication
use and adherence. In cases where standard treatments are not effective, referral to an
asthma specialist may be necessary to explore advanced therapeutic options, such as
biologic agents or bronchial thermoplasty.
Another critical aspect of preventing asthma-related deaths is the timely
management of acute exacerbations. Asthma action plans, which are individualized for
each patient, provide clear instructions on how to manage worsening symptoms and when
to seek emergency care. These plans are a crucial tool in preventing severe exacerbations
from progressing to life-threatening stages.
Healthcare providers must also stay informed about the latest developments in
asthma management and be vigilant in updating their clinical practices accordingly. This
includes staying current with the guidelines provided by NAEPP and GINA, which are
periodically updated to reflect new research findings and advancements in asthma care.
In conclusion, preventing deaths from asthma in hospitalized patients requires a
multifaceted approach that includes appropriate and timely therapy, patient education,
regular monitoring, and adherence to established guidelines. By following the
recommendations of NAEPP and GINA, healthcare providers can significantly reduce the
risk of fatal outcomes and improve the quality of life for patients with asthma.
Continuous efforts to educate patients, optimize treatment plans, and respond swiftly to
exacerbations are essential components of effective asthma management.
b. Etiology
Epidemiologic studies strongly support the concept of a genetic predisposition
plus environmental interaction to the development of asthma, yet the picture remains
complex and incomplete.11 Genetic factors account for 60% to 80% of the susceptibility.
Asthma represents a complex genetic disorder, in that the asthma phenotype is likely a
result of polygenic inheritance or different combinations of genes. Initial searches
focused on establishing links between atopy (genetically determined state of
hypersensitivity to environmental allergens) and asthma Genome-wide searches have also
found linkages with genes on chromosome 17q21 (such as ZPBP2, GSDMB, and
ORMDL3) and interleukin genes (IL33, IL1RL1/IL18R1, and IL2RB9) and HLA-DQ
and SMAD3 that are associated with epithelial barrier function and innate and adaptive
immune response abnormalities.9 Although genetic predisposition to atopy is a
significant risk factor for developing asthma, not all atopic individuals develop asthma,
nor do all patients with asthma exhibit atopy. Disparate phenotypes of asthma
(progressive or remodeled vs nonprogressive) are likely genetically determined.
Environmental risk factors for the development of asthma include socioeconomic
status, family size, exposure to secondhand tobacco smoke in infancy, and in utero,
allergen exposure, ambient air pollution, urbanization, viral respiratory infections
includingrespiratory syncytial virus (RSV) and rhinovirus, and decreased exposure to
common childhood infectious agents.12 The timing of, and exposure to, certain
environmental factors during early childhood in genetically susceptible individuals is
thought to predispose to the development of allergies and asthma by allowing the allergic
immunologic system (T-helper cell type 2 [Th2 ] [Th2 high asthma] lymphocytes) to
develop instead of the system to fight infections (T-helper type 1 [Th1 ] [Th2 low
asthma] lymphocytes).9,13 The first 2 years of life appear to be most important for the
exposures to produce an alteration in the immune response system.
Risk factors for early recurrent wheezing in children under three years of age,
particularly those associated with viral infections, are numerous and varied. Among these
risk factors are preterm birth, low birth weight, male gender, and parental smoking. Each
of these factors can contribute to a child's susceptibility to recurrent wheezing episodes,
which can be distressing for both the child and their caregivers.
Preterm birth is a significant risk factor for early wheezing. Infants born before 37
weeks of gestation often have underdeveloped lungs, which makes them more vulnerable
to respiratory infections and wheezing. The lungs of preterm infants may lack sufficient
surfactant, a substance that helps keep the airways open, making it more challenging for
them to breathe easily when they contract a viral infection.
Similarly, low birth weight is closely linked to respiratory issues. Babies who are
born with a weight significantly below the average for their gestational age may have
compromised lung function and smaller airway structures. These factors can contribute to
a higher incidence of wheezing and other respiratory difficulties in the early years of life,
especially when the infant encounters common respiratory viruses such as respiratory
syncytial virus (RSV) or rhinovirus.
Male gender has also been identified as a risk factor for early recurrent wheezing.
Studies have shown that boys are more likely to experience wheezing in infancy and
early childhood compared to girls. This may be due to anatomical and physiological
differences, such as narrower airways and a higher susceptibility to respiratory infections
in boys during early development.
Parental smoking is another critical factor contributing to early wheezing in
children. Exposure to tobacco smoke, whether through maternal smoking during
pregnancy or secondhand smoke after birth, can have detrimental effects on an infant's
respiratory health. Smoke exposure can impair lung development, increase inflammation,
and reduce the ability of the respiratory system to clear infections, all of which can lead
to more frequent and severe wheezing episodes.
However, it is important to note that this early pattern of recurrent wheezing is
primarily attributed to the smaller airways typical of infants and young children. As these
children grow, their airways enlarge and become more resilient, often leading to a
decrease in wheezing frequency. Consequently, the presence of these early risk factors
does not necessarily indicate a higher likelihood of developing asthma later in life.
While some children with recurrent wheezing may go on to develop asthma,
others may outgrow these symptoms as their respiratory system matures. The progression
from early wheezing to persistent asthma is influenced by a complex interplay of genetic,
environmental, and immunological factors. For instance, a family history of asthma or
allergies, early exposure to allergens, and a history of severe respiratory infections may
increase the likelihood of developing chronic asthma.
Research has shown that early intervention and management of recurrent
wheezing can improve outcomes and potentially reduce the risk of long-term respiratory
issues. This includes strategies such as reducing exposure to tobacco smoke, managing
viral infections promptly, and possibly using preventive medications for children at high
risk. Regular follow-up with healthcare providers can ensure that any persistent or
worsening symptoms are addressed promptly, and that children receive appropriate care
tailored to their individual needs.
In summary, while preterm birth, low birth weight, male gender, and parental
smoking are significant risk factors for early recurrent wheezing associated with viral
infections in children under three years of age, these factors do not necessarily predict the
development of asthma in later life. The early wheezing pattern is largely due to the
smaller and more vulnerable airways in young children, and many will see an
improvement as they grow. Understanding and addressing these risk factors can help in
managing early wheezing and improving respiratory health outcomes in young children.
Atopy is the predominant risk factor for children to have continued asthma.12
Asthma can begin in adults later in life. Occupational asthma in previously healthy
individuals emphasizes the effect of environment on the development of asthma.14 The
heterogeneity of the asthma phenotype appears most obvious when listing the diverse
protective and risk factors for asthma development. These various factors have relative
degrees of importance from patient to patient. Environmental exposures are the most
important precipitants of severe asthma exacerbations. Epidemics of severe asthma in
cities have followed exposures to high concentrations of aeroallergens.
Viral respiratory tract infections remain the single most significant precipitant of
severe asthma in children and are an important trigger in adults as well. These infections,
including those caused by rhinoviruses, respiratory syncytial virus (RSV), influenza, and
parainfluenza, can lead to significant inflammation and obstruction in the airways,
exacerbating asthma symptoms. Children, with their developing immune systems and
smaller airways, are particularly susceptible to these infections, which can rapidly
escalate from mild symptoms to severe asthma attacks requiring urgent medical attention.
In adults, viral infections can similarly provoke acute asthma exacerbations, though the
pattern and severity might vary depending on the individual's baseline asthma control and
overall health status.
In addition to viral infections, there are several other factors that can precipitate
asthma exacerbations. Air pollution is a major concern, especially in urban areas with
high levels of pollutants such as ozone, nitrogen dioxide, sulfur dioxide, and particulate
matter. These pollutants can irritate the airways, leading to increased inflammation and
bronchoconstriction, which can trigger asthma symptoms or exacerbate existing ones.
Prolonged exposure to polluted air can also make individuals more susceptible to
respiratory infections, creating a vicious cycle of worsening asthma control.
Emotional stress is another significant trigger for asthma exacerbations. Strong
emotions such as anxiety, anger, or even intense excitement can lead to hyperventilation
and changes in breathing patterns, which can precipitate bronchoconstriction in
susceptible individuals. The physiological response to stress, which involves the release
of stress hormones such as cortisol and adrenaline, can also influence immune and
inflammatory responses, potentially worsening asthma symptoms. Managing stress
through techniques such as mindfulness, meditation, and therapy can be beneficial for
individuals with asthma.
Physical exercise, while generally beneficial for overall health, can also trigger
asthma symptoms in some individuals, a condition known as exercise-induced
bronchoconstriction (EIB). During intense physical activity, rapid breathing through the
mouth can lead to cooling and drying of the airways, which can provoke
bronchoconstriction. This is particularly common in environments with cold or dry air.
However, with proper management, including pre-exercise use of bronchodilators and
appropriate warm-up routines, individuals with asthma can engage in physical activities
with minimal risk.
Occupational exposures are another important factor in asthma exacerbations.
Certain workplaces may expose individuals to respiratory irritants or allergens such as
dust, fumes, chemicals, and biological agents, which can trigger asthma symptoms.
Occupations at higher risk include those in construction, manufacturing, healthcare, and
agriculture. Occupational asthma can develop after prolonged exposure to these
substances, and management often involves minimizing exposure, using protective
equipment, and in some cases, changing job roles or environments.
Various medications and drugs can also precipitate asthma exacerbations. For
instance, nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin and ibuprofen can
induce asthma symptoms in some individuals, a condition known as aspirin-exacerbated
respiratory disease (AERD). Beta-blockers, commonly used for cardiovascular
conditions, can also cause bronchoconstriction in asthmatic patients. Therefore, it is
crucial for individuals with asthma to inform their healthcare providers about their
condition so that appropriate medications can be prescribed, and potential triggers can be
avoided.
In summary, while viral respiratory tract infections are the predominant trigger for
severe asthma exacerbations in children and a significant trigger in adults, there are
numerous other factors that can precipitate asthma symptoms. Air pollution, emotional
stress, physical exercise, occupational exposures, and certain medications all play roles in
exacerbating asthma. Understanding and managing these triggers through a combination
of environmental control, stress management, appropriate medication use, and lifestyle
adjustments are essential for maintaining optimal asthma control and preventing severe
exacerbations. Regular follow-up with healthcare providers and personalized asthma
action plans are crucial in achieving and maintaining good asthma management, allowing
individuals to lead healthy, active lives despite their condition.
c. Pathophysiology
Inhaled allergen challenge models contribute most to our understanding of acute
inflammation in asthma.9 Inhaled allergen challenge in allergic patients leads to an early
phase reaction that, in some cases, may be followed by a late-phase reaction. The
activation of cells bearing allergen-specific immunoglobulin E (IgE) initiates the early
phase reaction. It is characterized by the rapid activation of airway mast cells and
macrophages leading to the rapid release of pro-inflammatory mediators such as
histamine, eicosanoids, and reactive oxygen (O2 ) species that induce contraction of
airway smooth muscle, mucus secretion, and edema.9 The bronchial microcirculation has
an essential role in this inflammatory process. Inflammatory mediators induce
microvascular leakage with exudation of plasma in the airways.9 Acute plasma protein
leakage induces a thickened, engorged, and edematous airway wall and a consequent
narrowing of the airway lumen. Plasma exudation may compromise epithelial integrity,
and the presence of plasma in the lumen may reduce mucus clearance.9 Plasma proteins
also may promote the formation of exudative plugs mixed with mucus and inflammatory
and epithelial cells. Together these effects contribute to airflow obstruction.
Airway inflammation has been demonstrated in all forms of asthma, and an
association between the extent of inflammation and the clinical severity of asthma has
been demonstrated in selected studies.9 It is accepted that both central and peripheral
airways are inflamed. In asthma, all cells of the airways are involved and become
activated. Included are eosinophils, neutrophils, T cells, mast cells, alveolar macrophages
and dendritic cells, epithelial cells, fibroblasts, and bronchial smooth muscle cells. These
cells also regulate airway inflammation and initiate the process of remodeling by the
release of cytokines and growth factors. Chronic inflammation is associated with
nonspecific BHR and increases the risk of asthma exacerbations. Exacerbations are
characterized by increased symptoms and worsening airway obstruction over a period of
days or even weeks, and rarely hours. Hyper-responsiveness of the airways to physical,
chemical, and pharmacologic stimuli is a hallmark of asthma.3 BHR also occurs in some
patients with chronic bronchitis and allergic rhinitis.
Normal healthy subjects also may develop a transient BHR after viral respiratory
infections or ozone exposure. However, the degree of BHR in patients with asthma is
quantitatively greater than in other populations. Bronchial responsiveness of the general
population fits a unimodal distribution that is skewed toward increased reactivity;
individuals with clinical asthma represent the extreme end of this distribution. The degree
of BHR within asthma correlates with its clinical course and medication requirement
necessary to control symptoms.3 Patients with mild symptoms or in remission
demonstrate lower levels of BHR. The current understanding is that the BHR seen in
asthma is at least in part due to and correlative with the extent of airway inflammation.3
Airway remodeling also correlates somewhat with BHR.
Bronchial epithelial cells participate in mucociliary clearance and removal of
noxious agents; however, they also enhance inflammation by releasing eicosanoids,
peptidases, matrix proteins, cytokines, chemokines, and nitric oxide (NO).9 Epithelial
cells can be activated by IgE-dependent mechanisms, viruses, pollutants, or histamine. In
asthma, especially fatal asthma, extensive epithelial shedding occurs. The functional
consequences of epithelial shedding may include heightened BHR, release of the
chemokine eotaxin that attracts eosinophils, altered permeability of the airway mucosa,
depletion of epithelial-derived relaxant factors, and loss of enzymes responsible for
degrading pro-inflammatory neuropeptides. The integrity of airway epithelium may
influence the sensitivity of the airways to various provocative stimuli. Epithelial cells
also may be important in the regulation of airway remodeling and fibrosis.
Eosinophils play an effector role in asthma by releasing pro-inflammatory
mediators, cytotoxic mediators, and cytokines.9 Circulating eosinophils migrate to the
airways by cell rolling, through interactions with selectins, and eventually adhere to the
endothelium through the binding of integrins to adhesion proteins (vascular cell adhesion
molecule 1 [VCAM-1] and intercellular adhesion molecule 1 [ICAM-1]). As eosinophils
enter the matrix of the membrane, their survival is prolonged by interleukin 5 (IL-5) and
granulocyte-macrophage colony-stimulating factor (GM-CSF). On activation, eosinophils
release inflammatory mediators such as leukotrienes (LTs) and granule proteins to injure
airway tissue.
Mucosal biopsy specimens from patients with asthma contain lymphocytes, many
of which express surface markers of inflammation. There are two types of T-helper CD4+
cells. Th1 cells produce IL-2 and interferon-γ (IFN-γ), both essential for cellular defense
mechanisms. Th2 cells produce cytokines (IL-4, 5, and 13) that mediate allergic
inflammation. It is known that Th1 cytokines inhibit the production of Th2 cytokines, and
vice versa. It is hypothesized that allergic asthmatic inflammation results from a Th2 -
mediated mechanism (an imbalance between Th1 and Th2 cells).9 However, it has also
been observed that there exists a low Th2 cytokine phenotype of asthma in adults that
appears more resistant to usual therapies for asthma.
Th2 low asthma is described as neutrophilic asthma or mixed, pauci-granulocytic
asthma and is less well understood.18 Patients are typically less responsive to
corticosteroids, have fewer allergic symptoms, and are diagnosed later in life. The T-cell
population in the cord blood of newborn infants is skewed toward a Th2 phenotype.9,12
The extent of the imbalance between Th1 and Th2 cells (as indicated by diminished IFN-
γ production) during the neonatal phase may predict the subsequent development of
allergic disease, asthma, or both. It has been suggested that infants at high risk of asthma
and allergies should be exposed to stimuli that upregulate Th1 -mediated responses in
order to restore the balance during a critical time in the development of the immune
system and the lungs.12 The basic premise of the Th1 and Th2 imbalance is that the
newborn’s immune system needs timely and appropriate environmental stimuli to create
a balanced immune response. Factors that enhance Th1 -mediated responses include
infection with Mycobacterium tuberculosis, measles virus, helminths, and hepatitis A
virus; endotoxin exposure; increased exposure to infections through contact with older
siblings; and daycare attendance during the first 6 months of life. Restoration of the
balance between Th1 and Th2 cells may be impeded by frequent administration of oral
antibiotics, with concomitant alterations in GI flora. Other factors favoring the Th2
phenotype include residence in an industrialized country, urban environment exposure,
diet, and sensitization to house dust mites and cockroaches.12 Immune “imprinting” may
begin in utero by transplacental transfer of allergens and cytokines.
Mast cell degranulation is important in the initiation of immediate responses
following exposure to allergens.3 Mast cells reside throughout the walls of the respiratory
tract, and increased numbers of these cells (threefold to fivefold) have been described in
the airways of allergic asthmatics.9 Once binding of allergen to cell-bound IgE occurs,
mediators such as histamine; eosinophil and neutrophil chemotactic factors; LTs C4 ,
D4 , and E4 ; prostaglandins; platelet-activating factor (PAF); and others are released
from mast cells. Histologic examination has revealed decreased numbers of granulated
mast cells in the airways of patients who have died from acute asthma attacks, suggesting
that mast cell degranulation is a contributing factor. Sensitized mast cells are also
activated by osmotic stimuli to account for exercise-induced bronchospasm (EIB).
The primary function of alveolar macrophages in the normal airway is to serve as
“scavengers,” engulfing and digesting bacteria and other foreign materials. Macrophages
are found in large and small airways, ideally located for affecting the asthmatic response.
A number of mediators produced and released by macrophages have been identified,
including pro-inflammatory and anti-inflammatory cytokines, reactive oxygen species,
and eicosanoids.12 In addition, alveolar macrophages are able to produce neutrophil
chemotactic factor and eosinophil chemotactic factor, which in turn amplify the
inflammatory process.
The role of neutrophils in the pathogenesis of asthma remains somewhat unclear
because they reside in low numbers normally in the airway. Though they usually do not
infiltrate tissues showing chronic allergic inflammation, they are instrumental in the
inflammation arising from occupational exposures such as particulate matter, ozone, and
diesel exhaust. Neutrophils can be involved in late-phase inflammatory reactions.
However, high numbers of neutrophils have been observed in the airways of patients who
died from sudden-onset fatal asthma and in those with severe disease.20 This suggests
that neutrophils may play a pivotal role in the disease process, at least in some patients
with long-standing or corticosteroid-resistant asthma.17,20 The neutrophil also can be a
source for a variety of mediators, including PAF, prostaglandins, thromboxanes, and LTs,
that contribute to BHR and airway inflammation.
Associated with asthma for many years, histamine is capable of inducing smooth
muscle constriction and bronchospasm and is thought to play a role in mucosal edema
and mucus secretion.3 Lung mast cells are an important source of histamine. The release
of histamine can be stimulated by exposure of the airways to a variety of factors,
including physical stimuli (airway drying with exercise) and relevant allergens.9
Histamine is involved in acute bronchospasm following allergen exposure; however,
other mediators such as LTs are also involved. Besides histamine release, mast cell
degranulation releases ILs, proteases, and other enzymes that activate the production of
other mediators of inflammation. Several classes of important mediators, including
arachidonic acid and its metabolites (ie, prostaglandins, LTs, and PAF), are derived from
cell membrane phospholipids.
Once arachidonic acid is released, it can be metabolized by the enzyme
cyclooxygenase to form prostaglandins. Prostaglandin D2 is a potent bronchoconstricting
agent; however, it is unlikely to produce sustained effects and its role in asthma remains
to be determined. Similarly, prostaglandin F2 α is a potent bronchoconstrictor in patients
with asthma and can enhance the effects of histamine.3,9 However, its pathophysiologic
role in asthma is unclear. Another cyclooxygenase product, prostacyclin (prostaglandin I2
), is known to be produced in the lung and may contribute to inflammation and edema
owing to its effects as a vasodilator. Thromboxane A2 is produced by alveolar
macrophages, fibroblasts, epithelial cells, neutrophils, and platelets within the lung.9 It
may have several effects, including bronchoconstriction, involvement in the late
asthmatic response, and involvement in the development of airway inflammation and
BHR.
The 5-lipoxygenase pathway of arachidonic acid metabolism is responsible for the
production of the cysteinyl LTs. 9 LTC4 , LTD4 , and LTE4 are released during
inflammatory processes in the lung. LTs D4 and E4 share a common receptor (LTD4
receptor) that, when stimulated, produces bronchospasm, mucus secretion, microvascular
permeability, and airway edema, whereas LTB4 is involved with granulocyte chemotaxis.
Thought to be produced by macrophages, eosinophils, and neutrophils within the lung,
PAF is involved in the mediation of bronchospasm, sustained induction of BHR, edema
formation, and chemotaxis of eosinophils.
Adhesion molecules are glycoproteins that facilitate infiltration and migration of
inflammatory cells to the site of inflammation. They have additional functions involved
in the inflammatory process aside from promoting cell adhesion, including activation of
cells and cell–cell communication, and promoting cellular migration and infiltration.3
Many adhesion molecules are divided into families on the basis of their chemical
structure. These families are the integrins, cadherins, immunoglobulin supergene family,
selectins, vascular adressins, and carbohydrate ligands.9 Those thought to be important in
inflammation include the integrins, immunoglobulin supergene family, selectins, and
carbohydrate ligands, including ICAM-1 and VCAM-1.9 Adhesion molecules are found
on a variety of cells, such as neutrophils, monocytes, lymphocytes, basophils,
eosinophils, granulocytes, platelets, endothelial cells, and epithelial cells, and can be
expressed or activated by the many inflammatory mediators present in asthma.
The mucociliary system is the lung’s primary defense mechanism against irritants
and infectious agents. Mucus, composed of 95% water and 5% glycoproteins, is produced
by bronchial epithelial glands and goblet cells.9 The lining of the airways consists of a
continuous aqueous layer controlled by active ion transport across the epithelium in
which water moves toward the lumen along the concentration gradient. Catecholamines
and vagal stimulation enhance the ion transport and fluid movement. Mucus transport
depends on its viscoelastic properties. Mucus that is either too watery or too viscous will
not be transported optimally. The exudative inflammatory process and sloughing of
epithelial cells into the airway lumen impair mucociliary transport. The bronchial glands
are increased in size and the goblet cells are increased in size and number in asthma.
Expectorated mucus from patients with asthma tends to have a high viscosity. The
mucous plugs in the airways of patients who died in status asthmaticus are tenacious and
tend to be connected by mucous strands to the goblet cells. Asthmatic airways also may
become plugged with casts consisting of epithelial and inflammatory cells. Although it is
tempting to speculate that death from asthma attacks is a result of the mucous plugging
resulting in irreversible obstruction, there is no direct evidence for this. Autopsies of
asthmatics who died from other causes have shown similar pathology. In addition, some
patients who have died of sudden severe asthma did not show the characteristic mucous
plugging on necropsy.
The airway smooth muscle extends from the trachea through the respiratory
bronchioles. When expressed as a percentage of wall thickness, the smooth muscle
represents 5% of the large central airways and up to 20% of the wall thickness in the
bronchioles. Total smooth muscle mass decreases rapidly past the terminal bronchioles to
the alveoli, so the contribution of smooth muscle tone to airway diameter in this region is
relatively small. In the large airways of asthmatics, smooth muscle may account for 11%
of the wall thickness. It is possible that the increased smooth muscle mass of the
asthmatic airways is important in magnifying and maintaining BHR in persistent disease.
However, it appears that the hypertrophy and hyperplasia are secondary processes caused
by chronic inflammation and are not the primary cause of BHR.
The airway is innervated by parasympathetic, sympathetic, and nonadrenergic
inhibitory nerves.3 Parasympathetic innervation of the smooth muscle consists of efferent
motor fibers in the vagus nerves and sensory afferent fibers in the vagus and other
nerves.21 Normal resting tone of human airway smooth muscle is maintained by vagal
efferent activity. Maximum bronchoconstriction mediated by vagal stimulation occurs in
the small bronchi and is absent in the small bronchioles. The nonmyelinated C fibers of
the afferent system lie immediately beneath the tight junctions between epithelial cells
lining the airway lumen.21 These nerve endings probably represent the irritant receptors
of the airways. Stimulation of these irritant receptors by mechanical stimulation,
chemical and particulate irritants, and pharmacologic agents such as histamine produces
reflex bronchoconstriction.
The nonadrenergic, noncholinergic (NANC) nervous system has been described
in the trachea and bronchi. Substance P, neurokinin A, neurokinin B, and vasoactive
intestinal peptide (VIP) are the best characterized neurotransmitters in the NANC
nervous system.9 VIP is an inhibitory neurotransmitter. Inflammatory cells in asthma can
release peptidases that can degrade VIP, producing exaggerated reflex cholinergic
bronchoconstriction. NANC excitatory neuropeptides such as substance P and neurokinin
A are released by stimulation of C-fiber sensory nerve endings. The NANC system may
play an important role in amplifying inflammation in asthma by releasing NO.
NO is produced by cells within the respiratory tract. It has been thought to be a
neurotransmitter of the NANC nervous system.22 Endogenous NO is generated from the
amino acid L-arginine (L-Arg) by the enzyme NO synthase.22 Three isoforms of NO
synthase exist. One isoform is induced in response to pro-inflammatory cytokines,
inducible NO synthase (iNOS), in airway epithelial cells and inflammatory cells of
asthmatic airways.22 NO produces smooth muscle relaxation in the vasculature and
bronchials. However, it appears to amplify the inflammatory process and is unlikely to be
of therapeutic benefit. Investigations measuring the fraction of exhaled NO (FeNO)
concentrations have suggested that it may be a useful measure of ongoing allergic lower
airway inflammation in patients with asthma and for guiding asthma therapy.
Viral respiratory infections are primarily responsible for exacerbations of asthma,
particularly in children under age 10.15 Children aged 5 or younger may have wheezing
(which may or may not be asthma) associated with upper respiratory tract infections up to
six to eight times per year.2 Infants are particularly susceptible to airway obstruction and
wheezing with viral infections because of their small airways. Approximately 30% to
40% of infants who have severe RSV bronchiolitis will have recurrent wheezing but the
subsequent prevalence of asthma is 5% to 10% in children.15 The most common cause of
exacerbations in both children and adults is the rhinovirus, which is the most frequent
virus associated with the common cold and distributed worldwide.15 Other viruses
isolated include RSV, parainfluenza virus, adenoviruses, coronavirus, and influenza
viruses. Certain viruses (RSV and parainfluenza virus) are capable of inducing specific
IgE antibodies, and rhinovirus can activate eosinophils directly in asthmatics.15 The
increase in asthma symptoms and BHR that occurs may last for days or weeks following
resolution of the symptoms of the viral infection. Evidence does not support a beneficial
effect of influenza vaccine for preventing asthma exacerbations from subsequent
influenza infections.3 However, patients with moderate-to-severe asthma should be
vaccinated against influenza annually.
The development and heterogeneity of persistent asthma is driven by complex
gene–environment interactions. The mechanisms for inducing symptoms are as varied as
the exposure factor and include both IgE- and cell-mediated reactions.2 The World
Allergy Organization (WAO) predicts an increase in the incidence and prevalence of
asthma due to environmental exposures from climate change.24 Greater temperature
variability, industrial pollution, more frequent forest fires, higher concentration of
ground-level ozone, increased trans-boundary movement of respiratory infectious agents,
and changes in aeroallergen distribution are all cited factors. Exposure to 0.2 ppm ozone
for 2 to 3 hours can induce bronchoconstriction and increase BHR in asthmatics.3,14
Sulfur dioxide in the ambient atmosphere is highly irritating and presumably induces
bronchoconstriction through mast cell or irritant-receptor involvement.3 Asthma
produced by repeated prolonged exposure to industrial inhalants is a significant health
problem. It has been estimated that occupational asthma accounts for 15% of all
asthmatic persons.
Observational studies demonstrate an association between increased stress and
worsening asthma, but the role is not clearly defined.3 Bronchoconstriction from
psychological factors appears to be mediated primarily through excess parasympathetic
input. Atropine has been shown to block experimental psychogenic bronchoconstriction.
Persons with asthma are more likely to have depression than those without asthma. The
episodic nature of both diseases may be related to abnormal expression of Th2 cytokines
that have effects in the brain as well as the airway. It is most important to emphasize to
both patients and parents that asthma is not an emotional disease. However, coping skills
may benefit the patient who becomes emotionally distraught during an asthma attack.
Disorders of the upper respiratory tract, particularly rhinitis and sinusitis, have
been linked with asthma for many years. As many as 40% to 50% of asthmatics have
abnormal sinus radiographs.3 The prevalence of allergic sensitization increases with
asthma severity; nasal polyposis is often seen in those with allergic rhinitis. It has been
postulated that transport of mucus chemotactic factors and inflammatory mediators from
nasal passages during allergic rhinitis into the lungs may accentuate BHR. However,
chronic sinusitis may just represent a nonbacterial coexisting condition with allergic
asthmatics because the histologic changes in the paranasal sinuses are similar to those
seen in the lung and nose.3 Thus, it would seem that treatment of upper airway disease
could optimize overall asthma control. However, a large study of children and adults
found that treatment of chronic sinonasal disease with intranasal corticosteroids for 6
months improved neither asthma control nor BHR, suggesting that the treatment of sinus
disease and asthma be managed separately.
Symptoms of gastroesophageal reflux disease (GERD) as well as asymptomatic
reflux are common in both children and adults who have asthma.3 Nocturnal asthma may
be associated with nighttime reflux.3 Reflux of acidic gastric contents into the esophagus
is thought to initiate a vagally mediated reflex bronchoconstriction.3 Also of concern is
that most medications that decrease airway smooth muscle tone may have a relaxant
effect on gastroesophageal sphincter tone. There is no benefit from treating asymptomatic
reflux in asthma. Treatment with proton pump inhibitors does not improve asthma control
even in those with documented reflux. Symptomatic reflux should be treated for its
general health benefits.
Asthma symptoms may vary significantly during different stages of the menstrual
cycle. Premenstrual worsening of asthma has been reported in 20% of women, whereas
worsening of pulmonary functions has been reported even in women not aware of
worsening symptoms. Women with premenstrual symptoms tend to be older, have a
higher body mass index, more severe asthma, and a longer duration of asthma.2 The
pathophysiology is uncertain because estrogen replacement in postmenopausal women
has been shown to worsen asthma, whereas estradiol and progesterone administration has
been variably reported to improve or have no effect on asthma in women with
premenstrual asthma. The clinical significance of menstruation-related asthma is still
unclear because some studies have reported that up to 50% of ED visits by women were
premenstrual, whereas others have reported no association with menstrual phase.
Pregnancy may cause worsening, improvement, or no change in asthma symptoms, and
the changes seem to occur with equal frequency. These changes are suspected to be
related to altered sex hormones, stress, and fetal antigens.
In the literature, documentation of food allergens as triggers for asthma is not
available.3 However, additives, specifically sulfites used as preservatives, can trigger
life-threatening asthma exacerbations. Beer, wine, dried fruit, and open salad bars, in
particular, have high concentrations of metabisulfites.3 Severe oral corticosteroid-
dependent patients should be warned about ingesting foods processed with sulfites.
Aspirin and other nonsteroidal anti-inflammatory drugs can cause severe asthma
exacerbations (aspirin-exacerbated respiratory disease).2 The mechanism is related to
cyclooxygenase-1 (COX-1) inhibition, and inhaled corticosteroids (ICSs) are the primary
preventive treatment although oral corticosteroids may be required; leukotriene receptor
antagonists (LTRAs) may be useful.2 The prevalence increases with age and severity of
asthma.3 The greatest frequency occurs in severe corticosteroid-resistant asthmatics in
their fourth and fifth decades who also have perennial rhinitis and nasal polyposis
(presence of several polyps).3 Other drugs that do not precipitate bronchospasm but that
prevent its reversal are the nonselective β-blocking agents.2,3 Children with vitamin D
insufficiency have been considered at greater risk of uncontrolled asthma (increased
hospitalizations, BHR, and eosinophil counts).29 Vitamin D helps regulate T cells and
improves their secretion of anti-inflammatory cytokines in response to corticosteroids.29
In adults with asthma, evidence of benefit for vitamin D supplementation is
inconclusive.2 There are no published data evaluating Vitamin D treatment in children
with asthma.
Epidemiologic data suggest that obesity increases the prevalence of asthma and
may reduce asthma control, although it may be difficult to distinguish obesity-induced
respiratory symptoms from true asthma symptoms particularly because obesity often
precedes the onset of asthma.30 Lung volume and tidal volume are reduced in obesity,
promoting airway narrowing. Obesity also produces lowgrade systemic inflammation that
may act on the lung to worsen asthma.30 The mechanism may be the release of adipose-
derived proinflammatory mediators such as IL-6, IL-10, eotaxin, tumor necrosis factor-α,
transforming growth factors-β1 , C-reactive protein, leptin, and adiponectin or a result of
common predisposing dietary factors. Although not all studies find relationship between
body mass index and asthma control, management of asthma in obese patients should
include weight loss measures.31 Additional comorbidities of obesity that may
independently contribute to asthma symptoms include obstructive sleep apnea, GERD,
and metabolic syndrome.
A thorough history that considers age, respiratory symptoms (onset,
exacerbations, progression, variability, seasonality or periodicity, and persistence), past
history, and previous diagnoses and treatment and response to treatment, and that
includes discussion of social and occupational risk factors may identify relevant smoking
history or exposure to environmental tobacco smoke. The clinician is then faced with
distinguishing asthma from COPD. Some patients have clinical features of both, now
termed asthma COPD Overlap Syndrome (ACOS).2 Physical examination findings, lung
function measures, and radiology data are then combined with the history, to confirm this
syndromic diagnosis. GINA and the Global Initiative for Chronic Obstructive Lung
Disease provide recommendations for initial therapy of ACOS, if the differential
diagnosis is equally balanced between asthma and COPD.32 Referral for expert advice
and further diagnostic evaluation may be necessary.
A recent literature review has been published to characterize the prevalence of
Asthma-COPD Overlap Syndrome (ACOS) and to examine the effect of different disease
definitions on these prevalence estimates. This comprehensive review aims to provide
valuable insights that can guide decision making for refining the definition of ACOS and
for designing clinical trials aimed at developing effective treatments.
ACOS represents a complex clinical condition where patients exhibit features of
both asthma and chronic obstructive pulmonary disease (COPD). This overlap poses
challenges in diagnosis and management, as it combines the persistent airflow limitation
typical of COPD with the variability and reversibility of airflow obstruction seen in
asthma. Due to these complexities, the precise definition of ACOS has been subject to
debate within the medical community, leading to variability in reported prevalence rates.
The literature review meticulously analyzed a wide range of studies that utilized
different criteria for diagnosing ACOS. These criteria often include combinations of
clinical history, spirometry findings, response to bronchodilators, and biomarkers such as
eosinophil counts. The review found that the prevalence of ACOS varies significantly
depending on the specific definitions and diagnostic criteria employed in different
studies. For instance, some studies defined ACOS based on clinical symptoms and
history alone, while others incorporated more stringent spirometric parameters and
biomarker thresholds.
This variability in defining ACOS not only affects prevalence estimates but also
has implications for patient management and treatment outcomes. Inconsistent definitions
can lead to misclassification, potentially resulting in inappropriate treatment regimens
that do not adequately address the dual nature of the disease. For example, patients with
predominant COPD features may benefit more from bronchodilators and anti-
inflammatory treatments, whereas those with more pronounced asthma characteristics
might require a different therapeutic approach, including inhaled corticosteroids.
The review underscores the need for a standardized and universally accepted
definition of ACOS. A refined definition would facilitate more accurate identification of
patients, ensuring they receive the most appropriate and effective treatment. Moreover, a
clear and consistent definition is crucial for the design of clinical trials. It enables the
recruitment of homogeneous patient populations, which is essential for evaluating the
efficacy and safety of potential treatments. Such standardization can also improve the
comparability of study results across different research centers and geographic regions.
In addition to addressing diagnostic criteria, the literature review highlights the
importance of considering comorbidities and patient-reported outcomes in the
management of ACOS. Patients with ACOS often have multiple comorbid conditions
such as cardiovascular disease, diabetes, and depression, which can complicate treatment
and impact quality of life. Understanding the full spectrum of comorbidities associated
with ACOS is essential for developing comprehensive management plans that address all
aspects of the patient's health.
Furthermore, the review suggests that future research should focus on the
underlying pathophysiological mechanisms of ACOS. Identifying biomarkers and genetic
factors associated with the disease could lead to more targeted therapies. Personalized
treatment approaches based on a patient’s specific phenotype and genotype could
improve outcomes and reduce the burden of ACOS.
In conclusion, the recent literature review on ACOS prevalence and disease
definitions provides critical insights that can inform clinical practice and research. The
variability in ACOS definitions highlights the need for a standardized approach to
diagnosis and classification. Such standardization would not only improve patient care
but also enhance the quality and comparability of clinical research. By refining the
definition of ACOS and focusing on comprehensive management strategies, including
consideration of comorbidities and personalized treatment options, healthcare providers
can improve outcomes for patients with this challenging condition. Continued research
into the pathophysiological mechanisms of ACOS will further support the development
of effective, targeted therapies, ultimately leading to better health and quality of life for
affected individuals.
d. Clinical Presentation
Classic asthma is characterized by episodic and variable respiratory symptoms;
however, the clinical presentation of asthma is as diverse as the number of triggering
events (see “Clinical Presentation: Chronic Ambulatory Asthma” above). Although
wheezing is the characteristic symptom of asthma, the medical literature is replete with
the warning that “not all that wheezes is asthma.” A wheeze is a high-pitched, whistling
sound created by turbulent airflow through an obstructed airway, so any condition that
produces significant obstruction can result in wheezing as a symptom. In addition, “all of
asthma does not wheeze” is an equally justifiable warning. Patients may present with a
chronic persistent cough (cough variant asthma) as their only symptom.2,3 There is no
single diagnostic test for asthma. The diagnosis is based primarily on a good history.
The patient may have a family history of allergy or asthma or have symptoms of
allergic rhinitis, or atopic dermatitis.2,3 Reversibility of airway obstruction following
administration of a short-acting inhaled β2 -agonist or excessive variability in twice daily
PEF over 2 weeks are diagnostic criteria.2 Patients with normal values of spirometry can
be challenged by exercise or substances that produce bronchoconstriction, such as
methacholine or mannitol, to determine if they have BHR, but, again, positive challenges
are not diagnostic. Newer tests of inflammation in the airways such as induced sputum
eosinophil and/or neutrophil counts and FeNO measurements are consistent with but not
diagnostic of asthma.
Uncontrolled asthma, with its inherent variability, can progress to an acute state
where inflammation, airway edema, excessive mucus accumulation, and severe
bronchospasm result in a profound airway narrowing that is poorly responsive to usual
bronchodilator therapy2,3 (see “Clinical Presentation: Acute Severe Asthma” above).
Although this progression is the most common scenario, some patients experience rapid-
onset or hyper-acute attacks.2,3 Hyper-acute attacks are associated with neutrophilic as
opposed to eosinophilic infiltration and resolve rapidly with bronchodilator therapy,
suggesting that smooth muscle spasm is the major pathogenic mechanism.20 In most
cases, emergency department (ED) visits for acute severe asthma represent the failure of
an adequate therapeutic regimen to control persistent asthma. Underutilization of anti-
inflammatory drugs and excessive reliance on short-acting inhaled β2 -agonists are the
major risk factors for severe exacerbations.2,3 However, frequent exacerbations may
represent a specific phenotype of asthma. A blunted perception of airway obstruction
may predispose certain individuals to fatal asthma attacks.
During vigorous exercise, pulmonary function measurements (FEV1 and PEF) in
patients with asthma increase during the first few minutes but then begin to decrease after
6 to 8 minutes EIB is defined as a drop in FEV1 of 10% or greater from baseline (pre-
exercise value).19 Most studies suggest that many patients with persistent asthma
experience EIB.3 The exact pathogenesis of EIB is unknown, but heat loss and/or water
loss from the central airways appears to play an important role.19 EIB is provoked more
easily in cold, dry air, ambient ozone, and airborne particulate matter; alternatively,
warm, humid air can blunt or block it.19 Studies have demonstrated increased plasma
histamine, cysteinyl LTs, prostaglandins, and tryptase concentrations during EIB,
suggesting a role for mast cell degranulation.19 These findings led to the development of
inhaled mannitol, an osmotic agent, as an indirect pharmacologic bronchoprovocation test
to assist in the diagnosis of asthma.34 A refractory period following EIB lasts up to 4
hours after exercise in some patients. During this period, repeat exercise of the same
intensity produces either no decrease in pulmonary function or a drop of less than 50% of
the initial response.19 The refractory period is thought to be caused by an acute depletion
of mast cell mediators and time required for their repletion. EIB is believed to be a
reflection of increased BHR associated with asthma. A correlation, though not perfect,
exists between EIB and reactivity to histamine, methacholine, and mannitol.
Other patient groups with BHR (eg, after viral infection, cystic fibrosis, or allergic
rhinitis) show bronchoconstriction after exercise to a lesser degree (5%-10% drops) than
patients with asthma (15%-40% drops).19 Patients will not always demonstrate the same
sensitivity. During periods of remission, a decreased sensitivity to the same degree of
exercise is often observed. Finally, a number of children and adults with EIB are
otherwise normal, without symptoms or abnormal pulmonary function except in
association with exercise.3 Elite athletes have a higher prevalence of EIB than the general
population.
Worsening of asthma during sleep is referred to as nocturnal asthma. Patients with
nocturnal asthma exhibit significant falls in pulmonary function between bedtime and
awakening.3 Typically, their lung function reaches a nadir at 3 to 4 AM. Although the
pathogenesis of this phenomenon is unknown, it has been associated with diurnal patterns
of endogenous cortisol secretion and circulating epinephrine.3 Direct evidence for an
inflammatory component to nocturnal asthma includes increased circulating histamine
and activated eosinophils and LT excretion at night associated with increased BHR to
methacholine.3 Numerous other factors that may affect nocturnal worsening of asthma,
including allergies and improper environmental control, gastroesophageal reflux,
obstructive sleep apnea, and sinusitis, also must be considered when evaluating these
patients.3 Experts consider nocturnal symptoms to be a sign of inadequately treated
persistent asthma.3 Awakening from nocturnal asthma is a sensitive indicator of both
severity and inadequate control.
The NAEPP3 and GINA2 outline sound strategies for management and treatment
of asthma. However, the NAEPP Guidelines for the Diagnosis and Management of
Asthma was last published in 2007 as the EPR3.3 Since that time, clinical practice
strategies have changed and new drugs have been approved for marketing by the Food
and Drug Administration (FDA) that merit evaluation and inclusion as revision to the
guidelines. At this time, a complete update to the guidelines is not planned. However,
updates on selected topics will be published in 2020. The GINA guidelines are updated
every few years, and thus, GINA is more current (updated in 2018), and describes levels
of evidence used in their report.2 Evidence level A provides a rich body of data
consisting of randomized controlled trials (RCTs) and meta-analyses; evidence level B
has a more limited body of data, but still relies on RCTs and meta-analyses; evidence C
includes outcomes of nonrandomized trials or observational studies; and evidence D
relies on panel consensus judgment. Therefore, the sections describing management of
chronic and acute asthma largely reflect the GINA guidelines.
The ICSs are considered the preferred long-term control therapy for persistent
asthma in all patients due to their potency and consistent effectiveness.2 Low- to
medium-dose ICSs reduce BHR, improve lung function, and reduce severe exacerbations
leading to ED visits and hospitalizations. They are more effective than theophylline or the
LTRAs.2,35 In addition, the ICS is the only therapy that reduces the risk of dying from
asthma.2,3 In the low to medium doses recommended by GINA, ICSs are safe for long-
term administration (see below).2,35 They do not appear to reduce airway remodeling
and loss of lung function found in some patients with persistent asthma. The ICSs do not
enhance lung growth in children with asthma, prevent the development of asthma in high-
risk infants, or induce remission of asthma as BHR and other measures of inflammation
return to pretreatment levels on discontinuation of therapy.36 The sensitivity and
consequent clinical response to ICSs can vary among patients.2,3 Although studies of the
alternative long-term control therapies (eg, LTRAs and theophylline) demonstrate
improvement in symptoms, lung function, and as-needed, short-acting inhaled β2 -agonist
use, they do not reduce BHR, suggesting minimal anti-inflammatory activity.2,3 The
evidence suggests minimal to no differences in efficacy between these alternatives. For
those patients inadequately controlled on low-dose ICSs either an increased dose of the
ICS or the combination of ICS and LABA is recommended in Step 3 to gain control of
more moderate persistent asthma.2 Alternatives could be the addition of LTRAs or
theophylline to ICSs.2 The addition of theophylline or LTRAs to ICSs is no more
effective than doubling the dose of the ICS.3 The combination of ICS/LABA is more
effective at reducing severe asthma exacerbations than doubling the dose of ICS in
moderate persistent asthma; increasing the dose of ICSs fourfold also will result in a
significant reduction in exacerbations.37,38 However, doses of ICSs in the high range
significantly enhance the risk of toxicity.39 Thus, high doses of ICSs plus LABA are
reserved for patients with severe persistent asthma.2,3 Although the addition of a third
controller medication is often used clinically in patients with severe persistent asthma
uncontrolled on high-dose ICS/LABA, there are limited studies evaluating this practice.2
LTRAs or theophylline added to high-dose combination ICS/LABA do not improve
outcomes.2 The addition of a biologic to therapy can reduce exacerbations by
approximately 30% to 50%.18,40 The addition of tiotropium bromide, however, to
ICS/LABA does not confer a lower risk of exacerbations.
Patients with documented allergen sensitization with clinical symptoms may also
be prescribed allergen immunotherapy given as subcutaneous injections or as sublingual
allergen immunotherapy. Treatment must be administered in a clinical setting that is
prepared to manage anaphylactic reactions. Because treatment may involve weekly
appointments for several years, patients need to carefully consider the burden of
treatment before initiating allergy immunotherapy. GINA provides general principles for
step-down of controller treatment.2 Consideration is warranted if symptoms have been
well controlled and lung function has been stable for more than or equal to 3 months
(Evidence Grade D). An appropriate time should be chosen (no respiratory infection, not
travelling, not pregnant). Engage the patient in this therapeutic trial, monitor with
symptoms and/or PEF, and schedule follow-up (Evidence Grade D). Stepping down ICS
doses by 25% to 50% at 3 month intervals is considered feasible and safe for most
patients (Evidence Grade B). This GINA approach emphasizes three components2 :
ASSESS—documentation of symptom control and risk factors, and if these are
uncontrolled, check inhaler technique and adherence, and consider whether symptoms are
due to a comorbid condition such as allergic rhinitis, GERD, or obesity rather than
asthma. ADJUST therapy (up or down)—both drug therapy and nonpharmacological
strategies; treat modifiable risk factors. REVIEW RESPONSE—assess and optimize
asthma control about every 3 months.
The management of asthma in children younger than 5 years of age follows the
same stepwise approach as in older children and adults but many treatments have not
been studied adequately. Thus, many of the recommendations in this age group are
extrapolated from older children and adults.2 The primary differences in management are
that no controller treatment is necessarily indicated for Step 1 and the recommended
treatment in Step 3 is doubling the dose of ICS rather than adding LABA as is
recommended for older children and adults; ICS/LABA have not been shown to reduce
the risk of exacerbation or improve symptom control compared to the same dose of ICS
alone.2 Most of the available ICS have been studied in young children but not all have
marketing approval from the FDA in this age group. Lack of an approved indication in
children under 5 years of age could affect insurance coverage for specific products. ICSs
are available as MDI, DPI, and nebulized formulations but the preferred method of
delivery is by MDI with a valved spacer and facemask, if needed.2 Smaller spacers (less
than 350 mL) are preferred because 5 to 10 breaths after actuation are required to inhale
the complete dose. It is also recommended to not change the spacer type once a child is
stable on a specific dose of ICS due to large differences in delivery between devices.2
ICS use, even with low doses, causes reductions in growth velocity in children that are
clinically important.
Thus, the lowest effective should be used and height should be regularly
measured during treatment.42,43 Treatment of moderate-to-severe asthma exacerbations
may require use of oral corticosteroids but high-dose nebulized budesonide administered
intermittently (1 mg twice a day for 7 days) at early signs of upper respiratory tract
infections was as effective at preventing severe episodes of wheezing in infants 12 to 53
months of age with recurrent wheezing as low-dose (0.5 mg daily) continuous therapy.44
The FDA approval for montelukast (an LTRA) in children younger than age 6 was based
on safety and pharmacokinetic studies establishing doses but not on efficacy, although
improvement in symptoms and as-needed bronchodilators was noted.3 Based on data
from older children, a small minority of children may respond better to montelukast than
ICS.3 ICSs are recommended as first-line therapy but the initial choice between a trial of
ICS or montelukast should be based on shared decision making between the provider and
caregiver.
The elderly are at highest risk from dying of asthma and there are multiple
contributing factors.2 As in very young children, there have been few prospective studies
evaluating drug therapies.2 In addition, the elderly have a high comorbidity burden which
may impact response to therapies differently than with younger patients, and which
contributes to the difficultly with adherence when multiple medications for different
diseases are given daily. Control of comorbid conditions (obesity, smoking, depression,
and rhinosinusitis) may be required to improve treatment outcomes.45 Arthritis, vision
impairment, and muscle weakness which may affect inspiratory flow should be
considered when selecting inhaler devices.2 In addition, the elderly may have difficulty
distinguishing breathlessness due to ageing or cardiovascular disease from symptoms of
asthma.2 Owing to the increased risk of osteoporosis and cataracts in the elderly, patients
requiring high doses of ICSs should have routine height measurements, bone mineral
density determinations, and ophthalmic examinations.2,3 Appropriate therapies for
prevention of osteoporosis should be instituted.2,3 ICS use may contribute to skin
bruising which is already common in the elderly.
A stepwise approach to managing asthma during pregnancy and lactation has
been published, with low-dose ICSs recommended as preferred treatment for mild
persistent asthma with the addition of a LABA if not adequately controlled.28,46
Budesonide is considered the preferred ICS to initiate because it has the greatest amount
of safety data, and the data are reassuring; however, patients who are well-controlled on a
particular ICS should remain on current treatment as changing doses could jeopardize
asthma control.28,46 Stepping down treatment should not be initiated during pregnancy
due to a risk of perturbations in asthma control.2 Albuterol is considered the preferred
rescue therapy.46 Conditions that may aggravate asthma such as allergic rhinitis,
sinusitis, and GERD should be aggressively treated.48 Pregnant women are particularly
susceptible to viral infections which may lead to exacerbations and worsening asthma
symptoms, and should be aggressively treated to avoid fetal hypoxia.2 Moderate-to-
severe exacerbations should be treated per usual treatment guidelines with a target
oxygen saturation of 95% (0.95).2 Hyperventilation during labor may induce
bronchoconstriction and should be treated with short-acting inhaled β2 - agonist.2
Fentanyl, rather than morphine, should be used for pain control as morphine may induce
histamine release and respiratory depression.
